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[X]  QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE

or

[  ]  TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE

(Exact Name of Registrant as Specified in its Charter)

(Address of Principal Executive Offices and Zip Code)

(Registrant's Telephone Number, Including Area Code)

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirement for the past 90 days.

Yes    X            No

Indicate by check mark whether the registrant is an accelerated filer (as defined in Rule 12b-2 of the Exchange Act)

Yes    X            No

Number of shares outstanding of the issuer's Common Stock, par value $.01 per share, as of May 09, 2005: 10,089,981 shares.

On December 22, 2004 we announced an agreement to acquire Optive Research, Inc. ("Optive"), a U.S. software company offering discovery informatics products complementary with our own to the pharmaceutical and biotechnology industry. We acquired Optive to maintain access to products presently being distributed by us and to gain access to new technologies being developed. The transaction was completed on January 5, 2005, for consideration including cash and stock. The acquisition was accomplished through a merger of a newly−formed, wholly−owned subsidiary of Tripos with and into Optive, with Optive surviving as our subsidiary. Under the terms of the agreement, we issued 600 shares of our common stock with a value of $3,183 (a portion of which is restricted and will vest evenly on a semi-annual basis over 2 years) and $4,750 in cash to Optive's former shareholders. The cash portion was funded by a group of new investors through the issuance of $3,500 of subordinated debt beari ng an interest rate of 11.42%, 112 shares of common stock with a negotiated value of $500 and warrants to purchase 156 shares of common stock at $4.48 per share. Optive's operating revenues prior to the acquisition were approximately $2,400, including nearly $900 of royalty payments made by us. The purchase price, including estimated direct acquisition costs, has been allocated as follows:

The allocation of purchase price is subject to change pending the completion of the Company's valuation of tangible and intangible assets acquired. The Company does not expect any such changes to be material.

Optive's results of operations are included in our consolidated statements of operations from the date of acquisition.

In November 2004, the Financial Accounting Standards Board ("FASB") issued Statement of Financial Accounting Standards ("SFAS") No. 151 "Inventory Costs-an amendment of ARB No. 43, Chapter 4" ("FAS 151"). FAS 151 clarifies the accounting for abnormal amounts of idle facility expense, freight, handling costs, and wasted material (spoilage) to require that these items be included as current-period charges and not included in overhead. In addition, FAS 151 requires that allocation of fixed production overheads to the costs of conversion be based on the normal capacity of the production facilities. The provisions in FAS 151 are effective for inventory costs incurred during fiscal years beginning after June 15, 2005. We are in the process of evaluating the requirements of FAS 151 but do not expect the adoption of FAS 151 to have a significant effect on our financial statements.

In December 2004, the FASB issued SFAS No. 123 (revised 2004), "Share-Based Payment" (FAS 123R"), which revises and replaces SFAS No. 123, "Accounting for Stock-Based Payment" and supercedes APB Opinion No. 25, "Accounting for Stock Issued to Employees." FAS 123R requires the measurement of all share-based payments to employees, including grants of employee stock options, using a fair-value based

method and the recording of such expense in our consolidated statements of operations. The pro-forma disclosures previously permitted under SFAS No. 123 will no longer be an alternative to financial statement recognition. The provisions of FAS 123R were to have been effective for reporting periods beginning after June 15, 2005. At the end of March, the SEC staff released Staff Accounting Bulletin No. 107 (SAB 107), providing guidance for implementing FASB Statement No. 123 (revised 2004), Share-Based Payment (Statement 123R). Subsequently, the Commission delayed the implementation dates for Statement 123R to the start of a Company's fiscal year. As a result, we will be required to comply with the provisions of FAS 123R beginning January 1, 2006. We are currently evaluating the requirements of FAS 123R, but because we are presently accounting for employee stock option grants in a footnote disclosure as permitted by SFAS No. 123, the adoption of FAS 123R will have an impact on our results of operations effective upon adoption.

The remainder of this report may contain certain statements that are forward-looking and involve risks and uncertainties. Words such as "expects", "anticipates", "projects", "estimates", "intends", "plans", "believes", variations of such words and similar expressions are intended to identify such forward looking statements. These statements are based on current expectations and projections made by management and are not guarantees of future performance. Therefore, actual events, outcomes and results may differ materially from what is expressed or forecast in such forward-looking statements. Among the factors that could cause actual results to differ materially from the forward-looking statements are set forth under the caption "Cautionary Statements -- Additional Important Factors to be Considered" in Item 7, Management's Discussion and Analysis of Financial Condition and Results of Operations ("MD&A") in Tripos' Form 10-K for 2004. Tripos undertakes no obligation to update any forward-looking statements in this Form 10-Q.

The following discussion should be read in conjunction with the audited consolidated financial statements and notes thereto.

We provide products and services to the pharmaceutical, biotechnology, and life science industries to support early stage research activities. Our offerings are applied principally to assist research chemists to make decisions about the most productive new compounds to make and test as potential therapeutics. Through our own chemistry laboratories, we can also make those compounds for our clients. Through strategic partnerships, we can also test compounds for our clients.

The industries that we serve are highly research driven. Industry trade publications state that mature pharmaceutical companies typically spend between 12% and 20% of their annual revenues on research in the search for new blockbuster drugs. This research process consists of several phases from early discovery of compounds of interest, through testing of the promising ones for activity and safety in animals, to final testing of these compounds in humans. Our offerings are most relevant to the initial phase of this activity. Our products and services are designed and intended to provide our pharmaceutical and biotechnology customers with improved ways to identify and select the most promising drug candidates to take forward into the more expensive and time consuming stages of the drug development process. Depending on the number of compounds that a particular company has in different stages of their new therapeutic pipeline, it may reduce or increase investment in the other phases of resear ch. Further, decisions by the pharmaceutical

industry concerning their research investments are strongly influenced by decisions by the various governments of the world regarding drug pricing and regulation.

Our software products are sold on a renewable license basis, typically with a term of one or three years. This business is generally predictable, as we have experienced high renewal rates in the past for licenses. Our management closely monitors license expirations and deploys sales staff to ensure the highest probability of renewals. Our service businesses, both informatics and chemistry, are much less predictable. The sales cycles for these offerings are typically long -- from six months to eighteen months -- and are highly influenced by factors in the macro-economic environment, including the general state of the pharmaceutical industry and the political situations in various parts of the world. To forecast potential business in these areas, our management strives to closely interact with the management of our customers and is closely involved in business development activities for service projects.

Large service contracts for pharmaceutical research, both informatics and chemistry, are complex and, because they are deployed in research applications where outcomes are uncertain, have a large risk component. Risk management in these projects begins with the definition of project requirements and continues through performance metrics and customer acceptance milestones. Due to the complexity of the projects and changing priorities within client organizations, it is typical that many decision points will arise that require management attention both at Tripos and at the client. To mitigate the project difficulties, we have developed a process focus and management monitors milestones in the project plan according to the process workflow. Despite these efforts, however, some projects are of sufficient complexity that they present challenges that require revisions to the project plan and scope.

Having been a public company spin-off in 1994 with limited capital, we have focused on profitability and cashflow. That said, the company has not always been profitable, but we have achieved profitability in certain years. Major investments, such as the recent expansion of our chemistry research laboratories in England, have been funded by the proceeds from the sale of certain investments, cash from operations, temporary use of debt capacity, and grant funding from the British government.

We license our discovery software products and post-contract support ("PCS") as either perpetual licenses or time-based licenses, typically one to three-year renewable contracts. The magnitude of these license fees is dependent on each customer's required usage levels, that is, the number of locations and individual users. Variations in licensing levels range from the low hundred-thousands up to several million dollars. The following are descriptions of our current sales models for discovery software:

Our integration of chemistry and biological data in the life sciences industries creates a revenue stream for discovery informatics services (software consulting). To serve this market, we maintain a staff of specialists who use our proprietary technology, such as MetaLayer, Lithium, FormsBuilder, Tripos Electronic Notebook, ChemCoreRIO and AUSPYX^TM technologies to configure customized solutions for data management. Revenue may be generated on a billable rate per day, or upon achievement of milestones or deliverables and is recognized as production activities are performed. These contracts may also generate substantial license fee revenue for our proprietary software technologies.

We develop and manufacture general screening compound libraries for sale to the life sciences industry for a fee per compound delivered. This has created the opportunity to offer follow-up discovery research methods to customers for design and synthesis of focused libraries for lead optimization. We also market a comprehensive research process to our life sciences customers for rapid and cost effective discovery. This process combines advanced informatics, chemistry and access to biology products and services, and proprietary discovery technologies for efficient lead development, refinement, and optimization resulting in a tightly integrated process to facilitate synergies in drug discovery.

We also act as a reseller of computer hardware. Hardware sales are generally made to facilitate our software customers' access to hardware components and are not a primary focus of our sales activities. We act as an authorized reseller and only order products on an "as needed" basis, and thus do not maintain any inventory. Margins on these sales are relatively modest.

We license discovery informatics tools to customers, provide ongoing support (including upgrades selected by customers) and provide informatics services to customers that enable integration of our existing and newly developed discovery tools to customers' discovery operations. We generally expense research and development costs associated with software enhancements and new functionality. Thus, a significant portion of the costs associated with development and enhancement of software is accounted for as research and development and not as a cost of software sales. Certain software development projects require substantial commitments of time and resources. Costs of these projects are capitalized upon achievement of technological feasibility and/or a working model according to Financial Accounting Standards Board ("FASB") Statement of Financial Accounting Standards ("SFAS") No. 86.

Quarterly expenses include the costs of research and development for software development and new chemistry research. We believe that core selling and administrative costs will remain generally consistent as a percentage of sales on an annual basis. Variability in quarterly expenses primarily occurs in relation to the level of revenues. This is due to sales compensation, bonuses, staffing for selling, general and administrative functions and for periodic marketing activities such as appearances at trade exhibitions.

Our revenues and expenses vary from quarter to quarter depending upon, among other things, the timing of customers' budget processes, the success of our sales efforts, the lengthy sales cycle and our ability to influence customers and prospective customers to make decisions to outsource portions of their discovery process, the size of the customers' capital expenditure budgets, the ability to produce compound libraries in a timely manner, market acceptance of new products and enhanced versions of existing products, the timing of new product introductions by us and other vendors, changes in pricing policies (ours, partners and other vendors), consolidation in customer base, client involvement in decision points in contracts related to project plans, our ability to accurately match contract costs to milestone or contract performance requirements on our larger collaborative arrangements, and changes in general economic and competitive conditions. Because much of our informatics product licens es and PCS revenue along with our contracted discovery research revenue is recognized ratably over multiple periods, fluctuations in our quarterly revenues and earnings are caused principally by sales of compounds or by achievement of milestones on specific projects. Our management team monitors quarterly business activity with the aid of sales pipeline reports and monthly financial reports.

Results of Operations (Amounts in thousands, except per share amounts)

Net sales for the first quarter of 2005 were $15,043 compared to $15,460 in 2004, a decrease of 3%. Discovery informatics products and support sales increased 5% to $6,263 in 2005 from $5,974 for same period in 2004. This increase is primarily attributable to a larger base of contract values from existing time-based license customers along with revenues from our recently acquired Optive Research subsidiary. Discovery informatics services revenues for the first quarter of 2005 decreased 7% to $668. The reduction in this area's revenues was attributable to an overall reduction in the number and size of ongoing projects in the current year. The timing of revenue recognition from discovery informatics services is typically subject to achievement of contractual milestones. Discovery research sales accounted for $8,102 in the first quarter of 2005 and $8,727 in the same period in 2004, a decrease of 7%. This decrease in discovery research business was attributed to lower levels of product ion on the four-year, $90 million strategic compound file enrichment and hit follow-up contract with Pfizer (the "Pfizer Contract") that was partially offset by incremental work for other customers. As previously disclosed, revenues from the Pfizer Contract were expected to be lower in 2005 than 2004 as the project moves toward completion. Hardware sales decreased by 77% to $10 for the

first quarter 2005 from $44 in 2004. We do not actively market hardware products, but rather facilitate customer demand when required.

Net sales for the Company's activities outside of North America represented approximately 80% for both three-month periods ending March 31, 2005 and 2004. North American net sales, accounting for roughly 20% of 2005 and 2004 total first quarter sales. Net sales in Europe decreased 5% for the first quarter of 2005 compared to 2004, and accounted for 74% and 76%, respectively, of total sales. This decrease in Europe is principally related to progress on the Pfizer strategic compound design and synthesis project that was contracted through our U.K. office. Net sales in the Pacific Rim increased by 27% for the first quarter of 2005 compared to the same period in 2004. The increase was driven primarily by incremental perpetual informatics licenses in 2005 versus 2004. The Pacific Rim accounted for 6% and 4% of net sales for three-month periods in 2005 and 2004, respectively.

Cost of sales for the three-month period ending March 31, 2005 increased 3% to $7,907 compared to $7,693 for the same period in 2004. Cost of sales as a percent of net sales was 53% and 50% for the three-month periods in 2005 and 2004, respectively. Driving the increase in cost of sales for the first quarter of 2005 was amortization of the informatics product-related intangibles acquired in the Optive Research transaction and incremental costs of handling our LeadQuest compound sales. The cost of sales of discovery research activities in 2004 were impacted by the adverse effect of foreign currency (U.S. dollar to Great Britain Pound). The currency effect in the first quarter of 2005 was less than that of the same period in 2004.

Gross profit margin for the first quarter 2005 declined to 47% of total net sales versus 50% in the first quarter of 2004. Principal contributors to the decrease in overall gross margin were higher royalties from certain discovery software sales, the recognition of zero margin from the milestone delivery under the Schering contract, higher costs to process small chemical compound orders and amortization of the product-related intangibles acquired with Optive Research, Inc. We will not recognize gross margin, if any, on the Schering discovery informatics consulting contract until the project is completed due to its historical experience of losses on the assignment. The majority of the discovery informatics service revenues in the first quarter of 2005 were attributable to the Schering contract. Gross profit for the company is also dependent on costs of chemical materials and overhead, the mix of internal versus third-party software product sales, foreign exchange rates and the compan y's ability to successfully deliver on informatics contracts.

Sales and marketing expenses decreased 6% to $2,945 for the first quarter of 2005 from $3,142 in the same period in 2004. Sales and marketing expenses as a percentage of net sales were 20% for both three-month periods in 2005 and 2004, respectively. The decrease in sales and marketing spending was attributable to lower employee costs and the expiration of certain consulting relationships.

Research and development expenses decreased by 32% to $1,921 from $2,828 and represented 13% and 18% of net sales for the three-month periods in 2005 and 2004, respectively. The decline in quarterly R&D expense year-over-year was attributable to reductions to staff in certain areas of our informatics group, capitalization of $600 of costs for development related to discovery informatics products that have achieved technological feasibility and inventoried costs related to our innovative Lead Discovery chemistry projects.

General and administrative expenses increased 5% to $1,965 in 2005 from $1,879 for the first quarter of 2004, respectively, and represent 13% and 12% of net sales for the corresponding periods. Higher administrative costs at our expanded U.K. chemistry facility more than offset expense reducution in other areas.

Interest expense and other income (loss), net decreased to a loss of $587 in the first quarter in 2005 from income of $42 in the same period in 2004. The 2005 losses resulted from a currency loss of $320, net interest expense of $360 (net of interest income), and recording of an unrealized loss of $88 on our pro-rata share of an investment held in the A.M. Pappas Life Science II fund. Offsetting these losses was a gain of $182 from the sale of shares of NuVasive, Inc. (a recent IPO distribution from the A.M. Pappas Life Science II fund). In the same period of 2004, other income was comprised of a gain of $144 on the sale of shares of Arena Pharmaceuticals, Inc. coupled with a small currency gain partially offset by net interest expense of $167. We completed the sale of our Arena holdings in the first quarter of 2004.

Income tax benefit was $71 for the first three-months of 2005 compared to $15 for the same period in 2004, which represent effective tax rates of 25% and 38%, respectively. The 25% effective tax rate for 2005 reflects management's current estimate of the distribution of earnings among the statutory jurisdictions in which we operate, realization of additional R&D tax credits in the U.K. and the utilization of certain net operating loss carryforwards in 2005.

Net cash provided by operations in 2005 was $1,553. The primary sources of cash were from reductions in accounts receivable of $5,565, reductions in inventory of $1,348 plus the add-back of non-cash depreciation and amortization, including the amortization of debt discount, of $1,522, combined. These increases of cash were partially offset by payments of accounts payable and accrued expenses of $3,049 along with additions to prepaid expenses of $1,618 with a reduction in deferred revenue of $1,675. Net cash provided by operations in 2004 was $9,142. Sources of operating funds for 2004 were net collections of accounts receivable of $4,677, reductions in prepaid expenses of $1,221, increased deferred revenue of $4,472 plus the add-back of non-cash depreciation and amortization expenses of a combined $677 and a net reduction in the amount of foreign currency forward contracts outstanding of $757. Operating funds used in 2004 were from a net loss of $25, changes in net deferred tax positio n of $243, reductions of accounts payable & accrued expenses of $2,251, less the pre-tax gain of $144 from the sale of shares of Arena Pharmaceuticals common stock. The primary differences in cashflow from operations year-over-year arises from higher prepaid royalties in 2005 and receipt of $3,600 advance funding of technology access fees (deferred revenue) in the first quarter of 2004.

Cash used in investing activities during 2005 totaled $6,241 and were for property and equipment acquisitions of $1,076, capitalized development costs for our discovery informatics software products of $599 and the cash used in the acquisition of Optive Research, Inc. of $4,779. These were partially offset by $338 of gross proceeds from the sale of NuVasive shares. Over the next 12 to 18 months, we will be required to fund the remainder of our investment commitment ($625) to the A.M. Pappas Life Science II Fund. Cash used in investing activities in 2004 was $1,093 generated principally from the acquisitions of capital expenditures of $1,101, investment in the A.M. Pappas Life Science Ventures II of $188 partially offset by the proceeds from the sale of Arena shares of $196.

For 2005, $5,057 of cash was generated through financing activities from the issuance of common stock of $500 and subordinated debt of $3,500 to fund part of the acquisition of Optive Research and the issuance of shares under our employee stock plans of $8. We had a net increase in outstanding borrowings on our line of credit with LaSalle Bank of $1,900 that were partially offset by payments on our mortgage and capital leases of $851. For the first three-month period in 2004, the net cash used in financing activities was $4,087, consisting of payments on bank loans and capital lease arrangements totaling $4,445, less proceeds from additional capital leases of $341 and the issuance of shares under our employee stock plans of $17.

Subsequent to March 31, 2005, the company and LaSalle Bank executed an amendment to the existing credit facility. The modified revolving credit facility is now $6,500, which is an increase of $500 in available credit. The maturity date on the mortgage loan has been extended from December 2005 to April 2008. All other terms and conditions, including covenants, remain unchanged. At March 31, 2005, we had borrowings outstanding of $2,500 on the line of credit that were included in short-term debt.

Activities over and above normal operations may require additional sources of funding that are not presently identified. However, we believe that with our cash, accounts receivable balances, projected cash flows from operations, access to available borrowings from LaSalle Bank, and incremental capital leases, if any, we will be able to meet our liquidity needs and capital expenditure requirements for at least the next twelve months. We expect that our capital expenditure requirements will be substantially lower than in recent years due to the completion of our chemistry laboratory expansion.

Despite current capital markets uncertainties, we may decide to seek additional financing to support our objectives to enhance product development, expand existing markets and enter new markets, expand our chemistry research laboratories, fund participation in new therapeutic collaborations, or enhance our capital base for other purposes. In making decisions regarding access to additional capital, we will consider the availability and terms of financing alternatives, as well as our objective to maintain financial flexibility to support planned and opportunistic growth of our business. Additional capital may be in the form of equity or debt securities, and may be raised in public offering or private placement transactions. See "Management's Discussion and Analysis of Financial Condition and Results of Operations - Liquidity and Capital Resources", "Cautionary Statements - Additional Important Factors to be Considered" and Note 12 of the Notes to Consolidated Financial Statements in our Annu al Report on Form 10-K for the year ended December 31, 2004 for a discussion of the credit facilities available to us.

For further discussion of the Company's critical accounting policies, please see the section entitled "Critical Accounting Policies" in Management's Discussion and Analysis of Financial Condition and Results of Operations in Form 10-K for the year ending December 31, 2004. In addition, with the acquisition of Optive, which closed in the first quarter of 2005, management has determined that the accounting policies related to goodwill and other intangible assets should be included as one of the Company's identified critical accounting policies. The cost of acquired companies is allocated first to their identifiable tangible and intangible assets based on estimated fair values. Costs allocated to identifiable intangible assets are generally amortized on a straight-line basis over the remaining estimated useful lives of the assets. The excess of the purchase price over the fair value of identifiable assets acquired, net of of liabilities assumed, is recorded as goodwill and is subject to i mpairment tests at least annually as required by Statement of Financial Accounting StandardsNo. 142, "Goodwill and Other Intangible Assets." If the impairment test indicates that the carrying value of goodwill exceeds its fair value, than an impairment loss would be required to be recognized in the consolidated statements of operations in an amount equal to the excess carrying value.

Periodic reports on Form 10-Q, Form 10-K and other filings with the Securities and Exchange Commission ("SEC") on Form 8-K and S-8, can be found on the Tripos web site at www.tripos.com under the heading Investor Relations - SEC Filings.

Our exposure to financial markets risk is limited to foreign exchange variances and fluctuations in interest rates. The Company may be subject to a significant impact from foreign exchange. The costs to perform the custom design and synthesis contract with Pfizer are incurred in British pounds sterling while we are compensated in U.S. dollars for much of the work. As a result, our gross profit may be adversely affected by the decline in the U.S. dollar against the pound. At times, we may mitigate this effect through foreign currency forward contracts whose mark-to-market gains or losses are recorded in "Other Income".

Our foreign exchange risk is presently limited to currencies that historically have exhibited only minor fluctuations although during 2004 and currently, these currencies have shown more significant variation. Assets outside the United States are primarily located in England. Our investments in foreign subsidiaries with a functional currency other than the U.S. dollar are not hedged. The net assets in foreign subsidiaries translated into U.S. dollars using the year-end exchange rates were approximately $15.5 million at December 31, 2004. The potential reduction in fair value resulting from a hypothetical 10% adverse change in foreign currency exchange rates would have been approximately $1.6 million at December 31, 2004. Any loss in fair value of permanently invested funds would be reflected in Other Comprehensive Income and would not impact our net income.

Our interest rate risk is attributable to borrowings under the line-of-credit and mortgage loan that are tied to the bank's prime rate or short-term LIBOR rates. We monitor our exposure to floating interest rate risk on line-of-credit borrowings along with the outstanding balance on the mortgage loan and may endeavor to mitigate this risk through the use of appropriate hedging instruments.

(a)   The Company's Chief Executive Officer and Chief Financial Officer have evaluated the effectiveness of the design and operation of the Company's disclosure controls and procedures (as defined under Rules 13a-15(e) and 15d-15(e) of the Securities Exchange Act of 1934, as amended) as of the end of the period covered by this report. Based upon that evaluation, the Company's Chief Executive Officer and Chief Financial Officer have concluded that the Company's disclosure controls and procedures are adequate and effective.

(b)   During the quarterly period covered by this report, there were no changes in the Company's internal control over financial reporting that have materially affected, or are reasonably likely to materially affect, the Company's internal control over financial reporting.

Item 1.     Legal Proceedings

          No updates. See "Contingent Liabilities" in the Notes to Unaudited Financial Statements above for a general description. Reference is made to the "Legal Proceedings" section of our Form 10-K for the year ending December 31, 2004 for a detailed description of legal proceedings.

Item 2.     Changes in Securities and Use of Proceeds

          None

Item 3.     Defaults upon Senior Securities

          None

Item 4.     Submission of Matters to a Vote of Security Holders

          None

Item 5.     Other Information

          None

Item 6.     Exhibits

Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

FOURTH AMENDMENT
TO
AMENDED AND RESTATED LOAN AGREEMENT

THIS FOURTH AMENDMENT TO AMENDED AND RESTATED LOAN AGREEMENT ("Fourth Amendment") is made and entered into as of this 14th day of April, 2005 by and among TRIPOS, INC., a Utah corporation ("Tripos"), TRIPOS REALTY, LLC, a Missouri limited liability company ("Tripos Realty;" Tripos and Tripos Realty are sometimes collectively referred to herein as the "Obligors"), and LASALLE BANK NATIONAL ASSOCIATION (the "Lender").

WHEREAS, pursuant to that certain Amended and Restated Loan Agreement, dated as of December 2, 2002, by and among the Obligors and Lender, Lender (i) established in favor of Tripos a revolving line of credit in the amount of $6,000,000, and (ii) made a Term Loan  to Tripos in the amount of $4,350,000, as amended by that certain First Amendment to Amended and Restated Loan Agreement dated as of October 16, 2003, that certain Second Amendment to Amended and Restated Loan Agreement dated as of April 19, 2004 and that certain Third Amendment to Amended and Restated Loan Agreement dated as of December 21, 2004 (as the same may be further amended, supplemented or otherwise modified from time to time, the "Loan Agreement"); and

WHEREAS, the Lender has agreed to the modification of certain provisions contained in the Loan Agreement and certain of the other Loan Documents upon the terms and conditions hereafter set forth.

NOW, THEREFORE, in consideration of the premises and the mutual covenants and agreements set forth herein and for other good and valuable consideration, the mutuality, receipt and sufficiency of which are hereby acknowledged, the parties hereto hereby agree as follows:

1. Definitions. All capitalized terms not otherwise defined herein shall have the meanings given to such terms in the Loan Agreement.

2. Amendments to Loan Agreement. The Loan Agreement is hereby amended as follows:

3. Conditions to Effectiveness. This Fourth Amendment shall become effective when and only when the Lender shall have received (i) this Fourth Amendment duly executed by the Obligors, (ii) a replacement Revolving Note in form reasonably satisfactory to Lender, (iii) evidence reasonably satisfactory to the Lender and its counsel that the transactions contemplated by the Fourth Amendment have been properly authorized, (iv) a Third Modification of Deed of Trust, Assignment of Rents and Security Agreement of even date herewith in form reasonably satisfactory to the Lender and (v) a Reaffirmation of Guaranty in a form reasonably satisfactory to Lender duly executed by Tripos Realty and Optive Research.

4. Representations and Warranties. Borrower and Tripos Realty hereby represent and warrant as follows:

(a) This Fourth Amendment and the Loan Agreement, amended hereby, constitute legal, valid and binding obligations of the Obligors and are enforceable against Obligors in accordance with their respective terms, except to the extent that the enforceability thereof may be limited by bankruptcy, insolvency, reorganization, moratorium or similar Laws affecting creditors' rights generally or by equitable principles of general application.

(b) Upon the effectiveness of this Fourth Amendment, Obligors hereby reaffirm all covenants, representations and warranties made in the Loan Agreement (except to the extent any representation or warranty relates to an earlier date in which case such representations and warranties are not being restated) to the extent the same are not amended hereby and agrees that all such covenants, representations and warranties shall be deemed to have been remade as of the effective date of this Fourth Amendment.

(c) No Event of Default or Default has occurred and is continuing or would exist after giving effect to this Fourth Amendment.

(d) The Covered Persons have no defense, counterclaim or offset with respect to the Loan Agreement or any of the other Loan Documents.

5. Effect on the Loan Agreement.

(a) Upon the effectiveness of this Fourth Amendment, each reference in the Loan Agreement to "this Agreement," "hereunder," "hereof," "herein" or words of like import shall mean and be a reference to the Loan agreement as amended hereby.

(b) Except as specifically amended herein, the Loan Agreement, the Loan Documents, and all other documents, instruments and agreements executed and/or delivered in connection therewith, shall remain in full force and effect, and are hereby ratified and confirmed.

(c) The execution, delivery and effectiveness of this Fourth Amendment shall not operate as a waiver of any right, power or remedy of Lender, nor constitute a waiver of any provision of the Loan Agreement, the Loan Documents, or any other documents, instruments or agreements executed and/or delivered under or in connection therewith.

7. Governing Law. This Fourth Amendment shall be binding upon and inure to the benefit of the parties hereto and their respective successors and assigns and shall be governed by and construed in accordance with the laws of the State of Missouri.

8. Headings. Section headings in this Fourth Amendment are included herein for convenience of reference only and shall not constitute a part of this Fourth Amendment for any other purpose.

9. Counterparts. This Fourth Amendment may be executed by the parties hereto in one or more counterparts, each of which taken together shall be deemed to constitute one and the same instrument.

IN WITNESS WHEREOF, this Fourth Amendment has been duly executed as of the day and year first written above.

TRIPOS, INC.

By: _________________________________

Name: B. James Rubin

Title: Senior Vice President & Chief

Financial Officer

TRIPOS REALTY, LLC

(as Obligor and acknowledged as Guarantor)

By: TRIPOS, INC., its sole member

By: ________________________________

Name: B. James Rubin

Title: Senior Vice President & Chief

Financial Officer

LASALLE BANK NATIONAL ASSOCIATION

By: ________________________________

Name: Tom Harmon

Title: Senior Vice President