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Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.
Nat Commun, 15(1):4885.
Inherited cardiomyopathies are common cardiac diseases worldwide, leading in thelate stage to heart failure and death. The most promising treatments againstthese diseases are small molecules directly modulating the force produced byβ-cardiac myosin, the molecular motor driving heart contraction. Omecamtivmecarbil and Mavacamten are two such molecules that completed phase 3 clinicaltrials, and the inhibitor Mavacamten is now approved by the FDA. In contrast toMavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility.Here, we reveal by X-ray crystallography that both drugs target the same pocketand stabilize a pre-stroke structural state, with only few local differences.All-atom molecular dynamics simulations reveal how these molecules producedistinct effects in motor allostery thus impacting force production in oppositeway. Altogether, our results provide the framework for rational drug developmentfor the purpose of personalized medicine.
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